1. Field of the Invention
The present invention relates to nor-seco-, bis-nor-seco- as well as tris-nor-seco- and even higher nor-seco-cucurbit[n]uril compounds, including racemates and enantiomers thereof, and methods of making and using the same.
2. Description of the Background
In 1905, Behrend and co-workers reported the condensation of glycoluril (1 eq.) and formaldehyde (2 eq.) under aqueous acidic conditions (HCl, 100° C.). The product of this reaction—known in the literature as Behrend's polymer—was insoluble in nearly all solvents, but could be recrystallized from hot sulfuric acid from which a well-defined substance was obtained. In 1981, Mock and co-workers reported the structural characterization of this substance as cucurbituril (CB[6]). In recent years, various cucurbit[n]uril, i.e., CB[n], compounds have been prepared, isolated and characterized as shown below in Scheme 1.

These CB[n] compounds, with their large cavity volumes, function as host compounds which bind a wide range of chemically and biologically important guest molecules. These CB[n] compounds may be described as “extroverted” inasmuch as the H-atoms convex on the face of the glycoluril rings point outward therefrom. CB[n] compounds participate in a variety of interesting applications as diverse as fluorophore stabilization, chemical sensing, supramolecular vesicles, supramolecular dendrimers, molecular machines and complex self-sorting systems. For a review of cucurbit[n]uril homologues and derivatives, see Lee, W. et al. Acc. Chem. Res. 2003, 36, 621-630, and Lagona, J. et al. Angew. Chem. Int. Ed. 2005, 44, 4844-4870.
Subsequent to Mock's pioneering work, the groups of Kim and Day independently performed the condensation of glycoluril (1 eq.) and formaldehyde (2 eq.) under milder conditions (e.g. 70-100° C.) and were able to isolate the macrocycles containing 5, 7, and 8 glycoluril rings (CB[5], CB[7], and CB[8]), respectively, by fractional recrystallization procedures (Kim, J. et al. JACS, 2000, 122, 540-541 and Day, A. I. et al. J. Org. Chem., 2001, 66, 8094-8100). The Day group also reported the isolation of the cucurbit[10]uril as its inclusion complex with cucurbit[5]uril (CB[5]@CB[10]), see Day, A. I. et al. Angew. Chem. Int. Ed., 2002, 41, 275-277. The Isaacs group subsequently reported a method to remove the CB[5] from the CB[5]@CB[10] complex and thus have isolated CB[10] in uncomplexed form (Liu, S. et al. JACS, 2005, 127, 16798-16799).
More recently, (bis)phthalhydrazides have been used as glycoluril surrogates in the formation of cucurbit[n]uril analogs. This approach allows for a tailor-made synthesis of cucurbit[n]uril analogs, having phthalhydrazide units in a macrocycle wall thereof, with control over the size, shape and chemical functionality of the formed cucurbit[n]urils to a level not previously possible. See U.S. Ser. No. 10/933,538. These analogs are described as extroverted cucurbit[n]urils inasmuch as substituents on the convex face of the glycoluril protrude outwards from the internal molecular cavity.
Even more recently, inverted CB[n] compounds were discovered. See Isaacs, L. et al., JACS, 2005, 127, 18000-18001. These compounds are characterized by having at least one pair of hydrogen atoms protruding into the internal cavity of the cucurbit[n]uril compounds and, as such, are diastereomers of the extroverted CB[n] compounds. Inverted cucurbit[n]urils have one or more “inverted” glycoluril rings where at least two H-atoms or other substituents on the convex face of the glycoluril rings point into the cavity of the macrocycle.
Inverted cucurbit[n]urils or i-CB[n] compounds have the following type of structure, wherein the protruding hydrogen atoms are conspicuous:

The recognition properties of these inverted macrocycles are modulated in a useful way, i.e., enhanced kinetics and selectivity for aromatic guests like p-xylylene diamine by the structural change resulting therefrom. We determined that the use of p-xylylene diamine as probe of the crude CB[n] forming reaction mixture is particularly powerful since each cucurbit[n]uril or related compound gives a distinct resonance in the 6-7 ppm region of the 1H NMR spectrum. This allows for the facile identification of individual CB[n]-type compounds in crude reaction mixtures containing many different CB[n]-type compounds.
However, a need exists for nor-seco-type cucurbit[n]urils as these compounds lack —CH2— groups rendering their internal cavities more open and, thus, more responsive, for example, to guest compounds intended for use in the cavities.